1-(substituted benzyl)-2-(1h)pyrimidones and 1-(substituted benzyl)tetrahydro-2-(1h)pyrimidones

ABSTRACT

CERTAIN 1-(SUBSTITUTED BENZYL)TETRAHYDRO-2-(1H)PYRIMIDONES OF THE FORMULA:   1-((R-PHENYL)-CH2-)-PERHYDROPYRIMIDIN-2-ONE   WHEREIN R IN THE 4-POSITION IS CARBOMETHOXY, CARBOXY OR CARBOXAMIDO, AND IN THE 3-POSITION TRIFLUOROMETHYL POSSESS PHARMACOLOGICAL ACTIVITY AS ANTICONVULSANTS AND TRANQUILIZERS. THE CORRESPONDING 1-(SUBSTITUTED BENZYL)-2-(1H) PYRIMIDONES ARE USEFUL INTERMEDIATES IN THEIR PREPARATION.

United States Patent Claims ABSTRACT OF THE DISCLOSURE Certain l-(substituted benzyl) tetrahydro-2-(1H)pyrirnidon'es of the formulaiwherein R in the 4-position is carbomethoxy, carboxy, or carboxamido; inthe 3 -position trifluoromethyl possess pharmacological activity. as'anticonvulsants and tranquilizers.

The corresponding l-(substituted benzyl)-2-(1H) pyrimidohes are usefulintermediates in their preparation.

' is a' co ntinuation, of application Ser. No. 128,143, filed Mar. 25,1971, now abandoned.

This invention relates to chemical compounds. In particular it isconcerned with compounds of the formula:

An .oral dose of 200 mg./kg. of these compounds to mice intravenouslyreceiving 45 mg./kg. of pentylenetetrazol counteracts theconvulsive,property of pentylenetetrazol. Also a peroral dose of200-1600 mg./kg. of these compounds to mice elicits a tranquilizingeffect manifested by muscle relaxation and reduced spontaneous activity.

3,833,586 Patented Sept. 3, 1974 'Included within this invention arecompounds'of the formula:

p ce

wherein R in the 4-position is carbomethoxy, carboxy, or

canboxamido and in the 3-position trifluoromethyl which are useful inthe preparation of compounds of formula (I).

The preparation of the compounds of this invention can be accomplishedaccording to the following scheme:

In this scheme R is hydrogen and R has the significance previouslyascribed, Ar is optionally substituted phenyl and X is halogen. Thereaction sequence of this scheme is carried out using solvents inert tothe reactants such as methanol and dimethylformamide'. Reactionpromotants such as potassium carbonate and alkali metal iodides areadvantageous in effecting the condensation between the hydroxypyrimidineand the optionally substituted benzyl halide. Hydrogenation ispreferably effected using catalytic quantities of platinum oxide orpalladium on charcoal.

In order that this invention may be readily available to and understoodby those skilled in the art the following examples are appended:

EXAMPLE I Methyl p[(hexahydro-Z-oxo-l-pyrimidinyDmethyl] benzoate A.Methyl p-[(2-oxo-l-pyrimidinyl)methyHbenzoat A 74 g. (0.56 mole) portionof 2-hydroxypyrimidine hydrochloride in 800 ml. of methanol-was treatedwith 152 g. (1.12 mole) of K C0 46 g. (0.28 mole) of KI and 127 g. (0.56mole) of methyl p-bromomethylbenzoate. The reaction mixture wasrefluxed, with stirringjfor 24 hr. and filtered. The filtrate wasconcentrated to dryness under reduced pressure. The residue was taken upin 500 ml. of water and extracted with CHCI The CHCl3 extract was driedover MgSO overnight, filtered and concentrated to dryness to give 46 g.(34%) of 'the ester, a light yellow solid, mp. 170-179". 7 e The aqueousphase of the extraction was adjusted-to pH 3-4 with' ml. of concentrated=I-ICl to give 74' g. (57%) of the acid, mp. 242-249". The ester wasrecrystallized from 500 ml. of aceto- Z; nitrile, m.p. 188-189". Yield28 g. (20%). g

. A 3 I: B. Methyl p-[(hexahydro An 18 g. (0.074 mole) portion of A.,150 ml. of methanol and 0.2 g. of Pt were placed in a 0.5 1. pressurebottle and subjected to hydrogenation at 40 p.s.i.g. The hydrogen uptakewas (theory: 13#) in 0.6 hr. The reduction mixture was diluted with 100ml. of methanol, warmed, decolorized and filtered. The filtrate wasconcentrated to dryness under reduced pressure to give 18 g. (100%) of alight yellow solid, mp. 176-179.

The product was recrystallized from 1.2 l. of acetonitrile, washed withacetonitrile, ether and dried, m.p. 177-180". Yield: 10 g. (56%).

Anal.

Calcd. for C H N O C, 62.89; H, 6.50; N, 11.29. Found: C, 62.87; H,6.48; N, 11.39.

EXAMPLE II p [(Hexahydro-Z-oxo-1-pyrimidinyl)methyl]benzamide A.p[(2-oxo-l-pyrimidinyl)methyllbenzamide A solution of 26 g. (0.11 mole)of the compound of Example I, A. in 790 ml. of methanol and 910 ml. ofconcentrated ammonium hydroxide was stirred for 4 days at roomtemperature and filtered. The white crystalline solid was washed withwater and air dried, m.p. 252-254. Yield: 8 g. (32%).

The filtrate was concentrated to dryness to give 16 g. (64%) of a lightyellow solid, m.p. 241-244".

B. p[ (Hexahydro-Z-oxo-l-pyrimidinyl) methyl] benzamide Anal.

Calcd. for C H N O C, 61.78; H, 6.48; N, 18.02. Found: C, 62.05; H,6.67; N, 17.63.

Example II-I 1-(m-Trifluoromethylbenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidone A. 1- (m-Trifluoromethylbenzyl) -2 1H) -pyrimidone A 17.0 g.(0.128 mole) portion of 2-hydroxypyrimidine hydrochloride in 75 ml. ofmethanol was treated with 35.5 g. (0.258 mole) of K CO 10.6 g. (0.064moOle) of KI and 25.0 g. (0.128 mole) of a-chloro-3-trifluoromethyltoluene. The reaction mixture was refluxed for hrs. and concentrated todryness under reduced pressure. The residue was taken up in 200 ml. ofwater and extracted with 250 ml. of chloroform. The chlorofrom extractwashed with H O, dried over MgSO (Darco) and filtered. The filtrate wasconcentrated under reduced pressure to give 31 g. (95%) of a tacky whitesolid. The crude prodnot was crystallized using v50 ml. of toluene, m.p.8588.

Yield 12.9 g: (40%).

B. 1-(m-Trifiuoromethylbenzyl)-3,4,5,6-tetrahydro- 2(1H)-pyrimidone A12.9 g. (0.051 mole) portion of 1-(m-trifluoromethylbenzyl)-2(1H)pyrimidone, 150 ml. of methanol, and 0.3g. of PtO were placed in a 0.5 1. pressure bottle andv subjected to,hydrogenation at 40p.s.i.g. The hydrogen up- ,take was 111# (theory:102#) in 1 hr. The reduction 2 oxo-l-pyrimi dinyDnietliyl] mixture waswarmed, decolorized, filtered and concen- The product was recrystallizedfrom? m of aceto- EXAMPLE IV P-[ (Hexahydro-2-oxol-pyrimidinyl) methyl]benzoic acid A 35 g. (0.15 mole) portion of p-[(2-oxo-1-pyrimidinyl)methyl]benzoic acid, ml..of methanol aiid 0;4 'g. of PtO were placed ina-0.5 l. pressure' 'hottle and subjected to hydrogenation at 40 p.s.i.g.The hydrogen uptake-*was 2319'; (theory: 26#) in 5.5 hr'g'The reductionmixtiirelwas warmed, decolorized, filtered andconcentrated 'tgdrynessunder reduced pressure. The off-white solidwasjitalg en up in 500 ml. ofwater. The pH of the'solution wasadjusted to pH 7-8 with 125 g. ofNaaHCO ,,r e sulting' in complete solution. The solution was filtered,adjustedtdpH :3-4 with ml. of acetic .acid, stirred 1 hr. and filtered.The white crystalline solid was washed with-200 ml. of water, air driedand dried in a 60 oven for 6 hrs., m.p., 227-230. Yield: 25 g. (72%).

Anal.

Calcd. for C H N O C, 61.53; H, 6.02; N, 11,96. Found: C, 61.64; H,6.02; N, 11.80.

What is claimed is: 1. A compound of the'formula:

R wherein R is in the 4-po sition' carbomethoxy, carb'o'xyor carboxamidoand in the 3-po sition trifluoromethyl. j

2. The compound of Claim l'wherein'R is "S-trifluoromethyl. v V Y 3. Thecompound of Claim 1 wherein R is 4-carbomethoxy.

4. The compound of Claim 1 wherein R is 4-carboxy.

5. The compound of Claim 1 wherein R is 4-carboxamido. I

. 6. A compound of the formula:

wherein R is in the 4-position canbomethoxy, carboxy or carboxamido andin the 3-position trifiuoromethyl.

7. The compound of Claim 6 wherein R is 4-carbomethoxy.

8. The compound of Claim 6 wherein R is 4-carboxy. 9. The compound ofClaim 6 wherein R-i's 4-caflioxamido.

10. The compound of Claim 6 Wherein R is 3-tri-fiuoromethyl.

References Cited UNITED TATES PATENTS I q 7' 3,681,349 8/1972 Schwan etal. 1 R

RAYMOND RUS PrimaIyExaminer Q i

